Cancer is the second leading cause of death in the United States. The National Cancer Institute (NCI) of the U.S. National Institutes of Health (NIH) estimates that over 500,000 individuals will die from cancer and over 1.4 million individuals will be diagnosed with cancer in 2008. There is a global research effort to develop methods of treatment for cancer and to enhance the general understanding of how to prevent cancer, with countries like the United Kingdom, the Unites States, and others making cancer-related research a top priority. For example, the NIH has earmarked over 5 billion dollars in funding for cancer-related research for the 2008 fiscal year, almost twice the amount of funding provided for other serious diseases, such as HIV and heart disease.
There are over 100 different types of cancer. Despite the wide variety of cancers, most cancer-related deaths are caused by a few common cancers, such as lung cancer, colorectal cancer, and breast cancer. The NCI estimates that these three forms of cancer will cause over 250,000 deaths in 2008. While not as deadly as those cancers mentioned previously, skin cancer represents about half of all newly diagnosed cancers in the U.S., making it the most common type of cancer. Of the various types of skin cancer, melanoma is the rarest and most deadly. The American Cancer Society estimates that while melanoma accounts for only 4% of all diagnosed skin cancers in the U.S., it causes 79% of all skin cancer-related deaths.
Successful cancer treatment is often attributed to early diagnosis and treatment. A powerful method of diagnosing cancer is detecting tumor markers known to be associated with cancer. Tumor markers are substances, often proteins, which are produced by tumor cells, or other cells in the body in response to cancer. Tumor markers can be found in the blood, urine, on the surface of tumor cells, or on (or in) other, non-cancerous cells and tissues. Gangliosides have been identified as one type of marker associated with many tumors (Hakomori, 99 Proc. Natl. Acad. Sci. U.S.A. 10718 (2002)).
Gangliosides are glycosphingolipids with at least one sugar-linked sialic acid. These compounds are components of cell plasma membranes and are thought to play a central role in a variety of biological functions, such as cell growth, cell differentiation, cell signaling, and serving as receptors for microbial toxins (Jacques, et al. 4 Org. Biomol. Chem. 142 (2006)). Over 40 different gangliosides have been identified; however, a certain subset of these, GM3, GM2, GD3, and GD2, are commonly over-expressed by tumor cells (Id). Furthermore, gangliosides are reported to be highly immunogenic in humans. The combination of high immunogenicity and over-expression by tumor cells makes gangliosides a potential target for cancer therapeutics.
Ganglioside-specific monoclonal antibodies have been developed and, in some cases, examined for efficacy in humans (See generally, Azuma et al., 13 Clin. Cancer Res. 2745 (2007); Irie, et al., 53 Cancer Immunol. Immunother. 110 (2004); Irie and Morton, 83 Proc. Natl. Acad. Sci. U.S.A. 8694 (1986)). One of the earliest reports concerning a human, GD2-specific antibody was by Cahan, et al. (79 Proc. Natl. Acad. Sci. U.S.A. 7629 (1982)). Immunotherapy studies have shown that higher survival rates correlate with ganglioside-specific IgM, rather than IgG, for patients vaccinated with a melanoma vaccine (Jones et al., 66 J. Natl. Cancer Inst. 249 (1981)). Consistent with this finding, human studies involving IgM antibodies to gangliosides GD2 and GD3 have provided encouraging results for the use of such antibodies as a possible treatment for melanoma (Irie, et al., 53 Cancer Immunol. Immunother. 110; Irie and Morton, 83 Proc. Natl. Acad. Sci. U.S.A. 8694 (1986)).
IgM is one of five human antibody isotypes; IgG, IgA, IgE, and IgD are the others. IgM is typically the first antibody produced in a humoral immune response because the position of IgM heavy chain constant genes allows it to be produced without isotype switching (Charles A. Janeway, et al. Immunobiology 9-12 (5th ed. 2001)). Because IgM is often produced before genetic maturation occurs, this class of antibody isotype typically has lower affinity for a given antigen than other isotypes (Id). IgM compensates for low affinity by forming polymers, which increase the avidity of the antibody molecule (Id). Polymeric IgM usually forms as a pentamer associated with J-chain (a ˜15 kD molecule that promotes antibody polymerization); however, it can also polymerize as a pentamer or hexamer in the absence of J-chain (Id. at 4-19). In some instances, the polymeric state of IgM allows it to mediate highly effective activation of the complement pathway in the presence of pathogens. For example, J-chain-containing pentameric IgM is not usually effective in activating complement unless it undergoes a structural change when bound to an antigen (Id. at 9-17). In contrast, J-chain-free or hexameric IgM has been shown to activate complement up to 100-fold better than pentameric IgM (Weirsma et al., 160 J. Immunol. 5979 (1998)).
Cancer is a global health problem. Though progress has been made in treating various forms of this disease, improved therapeutics are needed. Immunotherapeutics are thought to have great potential for cancer therapy. An IgM antibody specific for an antigen expressed by cancer cells may prove to be an effective cancer therapeutic.